S296: IN VITRO ANALYSIS OF THE IMPACT OF INHIBITORS ON THE PROCOAGULANT EFFECTS OF BYPASS AGENTS OR HEMOSTATIC FACTORS IN COMBINATION WITH EMICIZUMAB
Authors: A. Dos Santos Ortas, E. García Arias-Salgado, E. Monzón Manzano, P. Acuña, M. T. Álvarez Roman, M. Martín Salces, M. I. Rivas Pollmar, E. García Pérez, M. Gutiérrez Alvariño, A. Gonzalez Ceberino, S. García Barcenilla, N. Butta, V. Jiménez Yuste
Journal: HemaSphere (2022)

Background: Emicizumab is a non-replacement treatment used in hemophilia A patients (PwHA). However, patients on prophylaxis with emicizumab exhibit mild-moderate bleeding phenotypes, thus Factor (F) VIII or bypassing agents (BPAs) are required to control breakthrough or perioperative bleeds. Increments of FIX levels, the main limiting factor for the FIXa-emicizumab-FX complex formation, also produce an increase of the emicizumab procoagulant effects similar to those obtained with FVIII or BPAs. Aims: To elucidate the impact of FVIII inhibitors in the efficacy of this hemostatic response, we compared the in vitro procoagulant effects of BPAs and FIX products in samples from emicizumab-treated patients with or without inhibitors. Methods: Blood from 21 patients on prophylaxis with emicizumab, 8 with inhibitor, was collected in tubes with CTI (Corn Trypsin Inhibitor) to prevent activation of the contact pathway. Spiking with therapeutic doses of 100 IU/dl octocog-alfa (rFVIII), BPAs [1 µg/ml eptacog alfa activated (rFVIIa); 5 U/dl activated prothrombin complex concentrate (aPCC)] or 100 IU/dl of plasma-derived FIX (pFIX), two standard-half-life (SHL) rFIX (nonacog-alfa and nonacog-gamma), and one extended-half-life (EHL) rFIX (albutrepenonacog-alfa) were tested. Clotting time (CT) was evaluated by Rotational Thromboelastometry (ROTEM) with whole blood, and Thrombin Peak by thrombin generation test (TGT) in plasma using low tissue factor concentration. Results: Emizicumab-treated samples showed prolonged CT values (Fig.1A) and lower thrombin peak levels (Fig.1B) than healthy controls and no significant differences were observed between samples with and without inhibitors. Addition of 100 IU/dl of all FIX products normalized the CT values similarly to the addition of the same dose of rFVIII. Nonacog-alfa was more efficient producing similar procoagulant effects than the addition of 1μg/ml rFVIIa or 5 U/dl aPCC. Reduction of CT was similar in samples from PwHA without or with inhibitors in all assayed conditions (Fig.1A). Higher thrombin peak values were also obtained by the addition of all the factors or BPAs tested by TGT but the procoagulant effect of all the recombinant FIX was significantly higher in samples with inhibitors (Fig.1B). Image:Summary/Conclusion: Procoagulant effect of BPAs with emicizumab was similar with or without inhibitors whereas thrombin generation increment produced by rFIX was enhanced in the presence of inhibitors. These results provide a rationale for investigating the concomitant use of rFIX and emicizumab in PwHA with inhibitor in breakthrough bleeding and surgery. Funding: ISCIII-FEDER (PI19/00631); CLS Behring; Catedra UAM-Roche; and Investigator-Initiated Reserach grant (no. IISR-2019-104361) from Baxalta GmbH, a wholly owned subsidiary of Takeda Pharmaceutical Comany Limited.